It is now widely accepted that exposure to adverse environmental conditions and lifestyle choices during pregnancy can result in fetal programming that underlies disease susceptibility in adulthood. One area that is understudied is the impact of maternal alcohol abuse on the offspring's susceptibility to cancer. A rapidly accumulating body of evidence indicates that many diseases must be understood in a life-long perspective, as trajectories that start at conception and surface upon clinical detection decades later. Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in prostate cancer risk. Several studies now identified alcohol intake positively correlated with the serum estrogen levels during pregnancy. Despite this information, very few studies have conducted to determine the association of alcohol promotion of estrogen level during pregnancy with the subsequent risk of prostate or other cancer risk in offspring. Our recent studies in rodents have provided evidence for higher incidence of prostate cancers in prenatal alcohol exposed animals. In addition, it has been shown that prostate tumors progress more frequently to a malignant phenotype in fetal alcohol-exposed rat offspring. Therefore, the study of the mechanism by which alcohol-induced fetal programming promotes prostate cancer is an important issue that needs investigation. We now have preliminary evidence that developmental reprogramming of the prostate by alcohol may be mediated, in part, through ESR1 activated transcriptional machineries. The objectives of the present application are to characterize in detail the transcriptional alterations in the prostatic tissues that result from early-life alcohol exposures and to determine if they are involved in predisposition to carcinogenesis. Hence, we propose to determine if the estrogen receptor 1-activation will promote while blocking estrogen receptor activity will suppress fetal alcohol-induced transcriptional responses and tumor susceptibility. We propose to use ChIP-seq to identify sites of occupancy for estrogen receptor 1 and RNA-seq to determine changes in gene expression in the prostate induced by fetal alcohol. Additionally, immunocytochemical and histopathological approaches will be employed to measure the growth and progression of prostatic tumors. The proposed studies employ an integrated approach that include the investigation of genome-wide changes in estrogen receptor 1 binding and gene expression caused by fetal alcohol exposure in the effected tissue during carcinogenesis. These studies address an important issue if epigenetic/genomic imprinting of the prostate gland by early ethanol exposure augments the susceptibility to prostate cancer. These studies are highly innovative as they would be the first to identify the molecular pathway in the process of fetal alcohol programming of the prostate that increases the sensitivity to tumorigenesis.